Type 2 diabetes mellitus (DM) is the sixth leading cause of death in the United States. Recently type 2 DM has been linked to subacute chronic inflammation as shown by elevated levels of inflammatory cytokines like, interleukin (IL)-I [3, IL-6 and tumor necrosis factor (TNF)-ct in persons with pre- and frank diabetes. In addition, glucocorticoid levels are increased in type 2 DM indicating activation of the hypothalamic-pituitary-adrenal (HPA) axis. New research from our laboratory shows that the BKS.Cg-m +/+ Leprdb (db/db) mouse model of type 2 DM has marked alterations in sickness behavior and innate immunity. We found that db/db mice are hyper-responsiveness to lipopolysaccharide (LPS) demonstrating increased fever and reduced social exploration. We also observed that these mice are more sensitive to IL-1 [3 showing increased loss of social exploration when compared to similarly treated heterozygote control (db/+) mice. Importantly, we have identified potential mechanisms to account for these abnormalities. These causes include hyperinsulinemia-induced serine phosphorylation of insulin receptor substrates (IRSs) blocking cytokine action and hyperglycemia-dependent protein kinase C (PKC)8 activation negatively regulating innate immunity. Therefore, the objective of this research project is to examine the hypothesis that type 2 DM induces a stress disorder that enhances brain responsivity to pro-inflammatory cytokines. The long-term goal of this project is to understand the mechanism by which type 2 DM augments innate immunity, inflammation and sickness behavior. These objectives and goals will be pursued in the following four Specific Aims. In Objective 1, we will examine the physiologic cause of increased fever and loss of social exploration in LPS-challenged db/db mice. In Objective 2, we will determine how hyperinsulinemia in pre-diabetes negatively regulates signaling of the anti-inflammatory cytokine IL-4. In Objective 3, we will investigate the mechanism by which hyperglycemia augments innate immunity. In Objective 4, we will use a pharmacologic approach to reduce susceptibility to increased fever and sickness behavior in db/db mice. These studies are needed to understand how diabetes-associated chronic inflammation affects the neuroimmune system. This is a revised submission of application 1 R01 DK064862-01 that was originally Emphasis Panel ZRG1 IFCN-2.